Thyroid cancer is the most common endocrine malignancy with a rapidly rising incidence in recent years. There are several major diagnostic, prognostic, and therapeutic challenges encountered currently in the management of this cancer. To overcome them needs the development of novel effective management strategies, which in turn relies on better understanding of molecular mechanisms of thyroid cancer. It has been well established that the PI3K/AKT pathway plays a fundamental role in thyroid tumorigenesis. Considerable success has been achieved in our lab in recent years on the research theme ?Molecular Events in the PI3K/AKT Pathway in Thyroid Cancer, particularly in characterizing the genetic and epigenetic molecular events in this pathway in thyroid cancer. To extend and bring this research to a new high level, we propose here to pursue a genome-wide search for novel tumor-promoting genes of thyroid cancer that are epigenetically controlled through aberrant methylation by the PI3K pathway and are among the fundamental molecular players in thyroid tumorigenesis. Based on our strong preliminary data we hypothesize that genome-wide aberrations in methylation and hence expression of important genes driven by the PI3K pathway is a fundamental mechanism in thyroid tumorigenesis; in this process many of such genes epigenetically controlled by the PI3K pathway are themselves novel tumor suppressor genes and oncogenes that play an important role in thyroid tumorigenesis and represent novel therapeutic targets and diagnostic and prognostic molecular markers for thyroid cancer. In this context, we propose to pursue three Specific Aims on this project 1) To explore genome-wide CpG methylation alterations driven by the PI3K pathway and identify important genes epigenetically controlled, through such methylation alteration, by this pathway; 2) To test the oncogenic functions and roles of selected genes controlled epigenetically by the PI3K pathway and establish them as important candidate tumor suppressor genes or oncogenes in thyroid cancer; and 3) To test the clinical translational potential of the novel gene methylation markers identified for the diagnosis and prognostication of thyroid cancer. The project will be conducted using a recently upgraded comprehensive 850K CpG methylation microarray platform as well as our well-established high-throughput technical approaches and in vitro and in vivo experimental protocols. The proposed studies are in a research area of our strong expertise and will take advantage of our large thyroid biospecimen collection and clinicopathological database in achieving the study aims. This innovative proposal has a high potential to advance the field.